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Intestinal distension orchestrates neuronal activity in the enteric nervous
system of adult mice.
Authors Cavin JB, Wongkrasant P, Glover JB, Balemba OB, MacNaughton WK, Sharkey KA
Submitted By Submitted Externally on 3/10/2023
Status Published
Journal The Journal of physiology, References
Year 2023
Date Published 2/1/2023
Volume : Pages Not Specified : Not Specified
PubMed Reference 36752210
Abstract The enteric nervous system (ENS) regulates the motor, secretory and defensive
functions of the gastrointestinal tract. Enteric neurons integrate mechanical
and chemical inputs from the gut lumen to generate complex motor outputs. How
intact enteric neural circuits respond to changes in the gut lumen is not well
understood. We recorded intracellular calcium in live-cell confocal recordings
in neurons from intact segments of mouse intestine in order to investigate
neuronal response to luminal mechanical and chemical stimuli. Wnt1-, ChAT- and
Calb1-GCaMP6 mice were used to record neurons from the jejunum and colon. We
measured neuronal calcium response to KCl (75 mM), veratridine (10 µM),
1,1-dimethyl-4-phenylpiperazinium (DMPP; 100 µM) or luminal nutrients (Ensure®),
in the presence or absence of intraluminal distension. In the jejunum and colon,
distension generated by the presence of luminal content (chyme and faecal
pellets, respectively) renders the underlying enteric circuit unresponsive to
depolarizing stimuli. In the distal colon, high levels of distension inhibit
neuronal response to KCl, while intermediate levels of distension reorganize
Ca2+ response in circumferentially propagating slow waves. Mechanosensitive
channel inhibition suppresses distension-induced Ca2+ elevations, and
calcium-activated potassium channel inhibition restores neuronal response to
KCl, but not DMPP in the distended colon. In the jejunum, distension prevents a
previously unknown tetrodotoxin-resistant neuronal response to luminal nutrient
stimulation. Our results demonstrate that intestinal distension regulates the
excitability of ENS circuits via mechanosensitive channels. Physiological levels
of distension locally silence or synchronize neurons, dynamically regulating the
excitability of enteric neural circuits based on the content of the intestinal
lumen. KEY POINTS: How the enteric nervous system of the gastrointestinal tract
responds to luminal distension remains to be fully elucidated. Here it is shown
that intestinal distension modifies intracellular calcium levels in the
underlying enteric neuronal network, locally and reversibly silencing neurons in
the distended regions. In the distal colon, luminal distension is integrated by
specific mechanosensitive channels and coordinates the dynamics of neuronal
activation within the enteric network. In the jejunum, distension suppresses the
neuronal calcium responses induced by luminal nutrients. Physiological levels of
distension dynamically regulate the excitability of enteric neuronal circuits.


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